Inge Petersen

Exceptional longevity does not result in excessive levels of disability

Late-life loss of independence in daily living is a central concern for the aging individual and for society. The implications of increased survival to advanced age may be different at the population level than at the individual level. Here we used a longitudinal multi-assessment survey of the entire Danish 1905 cohort from 1998 to 2005 to assess the loss of physical and cognitive independence in the age range of 92 to 100 years. Multiple functional outcomes were studied, including independence, which was defined as being able to perform basic activities of daily living without assistance from other persons and having a MiniMental State Examination (MMSE) score of 23 or higher. In the aggregate, the 1905 cohort had only a modest decline in the proportion of independent individuals at the 4 assessments between age 92 and 100 years: 39%, 36%, 32%, and 33%, with a difference between first and last assessment of 6% [95% confidence interval (CI), −1–14%]. For participants who survived until 2005, however, the prevalence of independence was reduced by more than a factor of 2, from 70% in 1998 to 33% in 2005 (difference, 37%; 95% CI, 28–46%). Similar results were obtained for the other functional outcomes. Analyses of missing data resulting from nonresponse and death suggest that the discrepancy between the population trajectory and the individual trajectory is caused by increased mortality among dependent individuals. For the individual, long life brings an increasing risk of loss of independence. For society, mortality reductions are not expected to result in exceptional levels of disability in cohorts of the very old.

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10−11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10−8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10−8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10−8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells

Exogenous and endogenous damage to DNA is constantly challenging the stability of our genome. This DNA damage increase the frequency of errors in DNA replication, thus causing point mutations or chromosomal rearrangements and has been implicated in aging, cancer, and neurodegenerative diseases. Therefore, efficient DNA repair is vital for the maintenance of genome stability. The general notion has been that DNA repair capacity decreases with age although there are conflicting results. Here, we focused on potential age‐associated changes in DNA damage response and the capacities of repairing DNA single‐strand breaks (SSBs) and double‐strand breaks (DSBs) in human peripheral blood mononuclear cells (PBMCs). Of these lesions, DSBs are the least frequent but the most dangerous for cells. We have measured the level of endogenous SSBs, SSB repair capacity, γ‐H2AX response, and DSB repair capacity in a study population consisting of 216 individuals from a population‐based sample of twins aged 40–77 years. Age in this range did not seem to have any effect on the SSB parameters. However, γ‐H2AX response and DSB repair capacity decreased with increasing age, although the associations did not reach statistical significance after adjustment for batch effect across multiple experiments. No gender differences were observed for any of the parameters analyzed. Our findings suggest that in PBMCs, the repair of SSBs is maintained until old age, whereas the response to and the repair of DSBs decrease.

Does more schooling reduce hospitalization and delay mortality? New evidence based on danish twins

Schooling generally is positively associated with better health-related outcomes—for example, less hospitalization and later mortality—but these associations do not measure whether schooling causes better health-related outcomes. Schooling may in part be a proxy for unobserved endowments—including family background and genetics—that both are correlated with schooling and have direct causal effects on these outcomes. This study addresses the schooling-health-gradient issue with twins methodology, using rich data from the Danish Twin Registry linked to population-based registries to minimize random and systematic measurement error biases. We find strong, significantly negative associations between schooling and hospitalization and mortality, but generally no causal effects of schooling.

Risk of Oral Clefts in twins

Background: Small studies have indicated that twinning increases the risk of oral cleft. Methods: We used data from a Danish national population-based cohort study to investigate whether twinning was associated with isolated oral cleft, and to estimate the twin probandwise concordance rate and heritability. Twins (207 affected/130,710) and singletons (7766 affected/4,798,526) born from 1936 through 2004 in Denmark were ascertained by linkage among the Danish Facial Cleft Database, the Danish Twin Registry, and the Civil Registration System. We computed oral cleft prevalence and prevalence proportion ratio for twins versus singletons, stratified for 3 subphenotypes. Probandwise concordance rates and heritability for twins were estimated for 2 phenotypes—cleft lip with or without cleft palate (CL/P) and cleft palate (CP). Results: The prevalence of oral cleft was 15.8 per 10,000 twins and 16.6 per 10,000 singletons (prevalence proportion ratio = 0.95; 95% confidence interval = 0.83–1.1). This prevalence was similar for monozygotic and dizygotic twins. The probandwise concordance rate was higher for CL/P for monozygotic twins than for dizygotic twins (50% vs. 8%, respectively). A similar contrast was present for CP. Recurrence risk for both types of clefts was greater in dizygotic twins than in non-twin siblings. Heritability estimates were above 90% for both CL/P and CP. Conclusions: No excess risk of oral cleft could be demonstrated for twins compared with singletons. The concordance rates and heritability estimates for both types of clefts show a strong genetic component.

The Danish Twin Registry: linking surveys, national registers, and biological information.

Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty-first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008-2011 and included both in-person assessments of 14,000+ twins born 1931-1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions.

The male-female health-survival paradox: a survey and register study of the impact of sex-specific selection and information bias.

PURPOSE This study examined whether the health-survival paradox could be due partially to sex-specific selection and information bias in surveys. METHODS The study is based on the linkage of three population-based surveys of 15,330 Danes aged 46-102 years with health registers covering the total Danish population regarding hospitalizations within the last 2 years and prescription medicine within 6 months before the baseline surveys. RESULTS Men had higher participation rates than women at all ages. Hospitalized women and women taking medications had higher participation rate compared with nonhospitalized women (difference=0.7%-3.0%) and female nonusers (difference=0.8%-7.6%), respectively, whereas no consistent pattern was found among men according to hospitalization or medication use status. Men used fewer medications than women, but they underreported medication use to a similar degree as did women. CONCLUSIONS Hospitalized women, as well as women using prescription medicine, were slightly overrepresented in the surveys. Hence, the study found some evidence that selection bias in surveys may contribute to the explanation of the health-survival paradox, but its contribution is likely to be small. However, there was no evidence for sex-specific reporting of medication use among study participants.

Education and Cognitive Ability as Direct, Mediating, or Spurious Influences on Female Age at First Birth: Behavior Genetic Models Fit to Danish Twin Data

The authors study education and cognitive ability as predictors of female age at first birth (AFB), using monozygotic and dizygotic female twin pairs from the Middle‐Aged Danish Twin survey. Using mediated regression, they replicate findings linking education (and not cognitive ability) to AFB. But in a behavior genetic model, both relationships are absorbed within a latent variable measuring the shared family environment. Two interpretations are relevant. First, variance in AFB emerges from differences between families, not differences between sisters within the same family. Second, even in a natural laboratory sensitive to genetic variance in female fertility—during demographic transition—the variance in AFB was nongenetic, located instead within the shared environment.

Genetic and environmental influences on odor identification ability in the very old

Odor identification ability and cognition were measured in a population-based cohort of 1,222 very old twins and singletons, including 91 centenarians. Heritability for identifying odors was low, in contrast to that for cognition. Common genes were found to contribute to both olfaction and cognition. In a multiple regression model, sex, age, cognitive function, and smoking, but not APOEε4 status, were significant predictors of the olfactory test scores (all ps < 0.001). This study, along with data from other studies, suggests that indices of heritability for odor identification decline with age, likely reflecting adverse environmental influences on the smell system.

Tremor in the elderly: essential and aging-related tremor

Isolated tremor in the elderly is commonly diagnosed as essential tremor (ET). The prevalence of tremor increases steeply with increasing age, whereas hereditary tremor is becoming less common. Moreover, late‐manifesting tremor seems to be associated with dementia and earlier mortality. We hypothesize that different entities underlie tremor in the elderly.